1. Field of the invention
This invention relates to a process for crosslinking of collagen by introduction of azide groups as well as tissues and biomaterials obtained by using the process.
2. The Prior Art
Replacement of a pathological cardiac valve in man now essentially resorts to two types of substitutes: mechanical prostheses and heterologous biological valves (also called heterografts or bioprotheses). If the former have the advantage of an almost unlimited life, they have as the main limitation a permanent thromboembolic risk requiring an anticoagulant treatment for life whose own (hemorrhagic) risks contribute in no small part to the morbidity and overall mortality observed in patients wearing these protheses.
On the contrary, bioprotheses today have clearly shown their slight thrombogenicity in the absence of anticoagulant treatment. On the other hand, their life is greatly burdened by the occurrence of tissue calcification which, alone or in association with fatigue lesions, lead to a reintervention in an average period of 6 years, this period moreover being shorter in younger patients.
Also, one of the main trends in research in the matter of artificial valves today is focused on the development of techniques making it possible to retard the deterioration of the bioprotheses.
Obviously, this deterioration is a multifactor phenomenon, some factors, "linked to the host," being difficult to control.
However, it clearly appears that the mode of treatment of the tissue at the time of production of the valve, a treatment on which it is possible to intervene, can play a primordial role.
At present, regardless of the animal origin of this tissue (aortic valves of hogs or bovine pericardium), its treatment almost always resorts, for the models of bioprotheses now on the market, to tanning techniques using glutaraldehyde (GTA).
Actually, the aptitude is known of this tanning agent for creating solid intermolecular bonds which enable the tissue thus treated to exhibit the required mechanical properties and to resist "in vivo" enzymatic degradation.
An additional argument for using glutaraldehyde is that, by the creation of bonds between the collagen molecules, it masks some antigenic determinants which makes it possible to limit the antigenicity of the tissue.
Although the exact relationship between glutaraldehyde and calcification has not yet been totally explained, there is certainly a causality relationship. Actually it appears, that contrary to untreated implants, implants of hog aortic valves treated with GTA severely calcify.
Further, it has been shown that hog aortic valves, or calf pericardium, both treated with GTA, calcify in the same way in rats (Schoen et al., Am. J. Path. 1986, 193, pp. 134-145).
Although factors regulating this calcification mechanism and depending on the host and the implant have been brought out (by Levy, Schoen, Howard et al), it has not yet been possible to determine the underlying mechanism of this calcification.
Moreover, the role of the collagen side groups was studied by Urist in 1966 and Glimcher in 1968.
Thus Urist was able to show that treatment of the tendon of a rat tail in solutions of inorganic salts such as CaCl.sub.2, SrCl.sub.2 or organic cations, which block carboxylic groups of side chains, effectively inhibit calcification of the tendons implanted in the hypercalcemic rat.
Glimcher tried to inhibit calcification of collagen of the bone in vitro by esterifying carboxylic groups. In this case, blocking of the groups inhibits calcification. However, a part of this inhibition would probably be due to dehydration of the tissue in methanol.